Use of bridged tricyclic amine derivatives as anti-ischemic agents

ABSTRACT

Certain bridged tricyclic amine compounds are described as being therapeutically effective in treatments of CNS disorders resulting from neurotoxic damage or neurodegenerative diseases, particularly those CNS disorders resulting from ischemic events. Compounds of particular interest for use as neuroprotective agents are those of the formula ##STR1## wherein each of R 1  and R 2  is independently selected from hydrido, loweralkyl, benzyl and phenyl; wherein each of R 1  through R 7  is independently selected from hydrido, loweralkyl, hydroxy, benzyl, phenyl, loweralkoxy, phenoxy, benzyloxy, halo and haloloweralkyl; wherein R 18  may be selected from hydrido, loweralkyl, cycloalkyl of five or six carbon atoms, cycloalkylalkyl of six or seven carbon atoms, phenyl, hydroxyloweralkyl, and heteroaryl selected from saturated or fully unsaturated heterocyclic rings containing five to seven ring members of which one or two ring members are nitrogen atom; wherein each X is independently one or more groups selected from hydrido, hydroxy, loweralkyl, benzyl, phenyl, loweralkoxy, phenoxy, haloloweralkyl, halo, and lower-alkanoyl; and wherein each of R 23  through R 30  is independently selected from hydrido, lower alkyl, benzyl, phenyl and halo; wherein R 18  together with one of R 23 , R 24 , R 29  or R 30  may form a fused heterocyclic ring containing five or six ring members; or a pharmaceutically-acceptable salt thereof.

FIELD OF THE INVENTION

This invention is in the field of clinical neurology and relatesspecifically to a class of therapeutically useful compounds,compositions and methods for management of neurotoxic damage orneurodegenerative diseases. For example, these compounds areparticularly useful for treating neurotoxic injury which follows periodsof hypoxia, anoxia or ischemia associated with stroke, cardiac arrest orperinatal asphyxia.

BACKGROUND OF THE INVENTION

Unlike other tissues which can survive extended periods of hypoxia,brain tissue is particularly sensitive to deprivation of oxygen orenergy. Permanent damage to neurons can occur during brief periods ofhypoxia, anoxia or ischemia. Neurotoxic injury is known to be caused oraccelerated by certain excitatory amino acids (EAA) found naturally inthe central nervous system (CNS). Glutamate (Glu) is an endogenous aminoacid which has been characterized as a fast excitatory transmitter inthe mammalian brain. Glutamate is also known as a powerful neurotoxincapable of killing CNS neurons under certain pathological conditionswhich accompany stroke and cardiac arrest. Normal glutamateconcentrations are maintained within brain tissue by energy-consumingtransport systems. Under low energy conditions which occur duringconditions of hypoglycemia, hypoxia or ischemia, cells can releaseglutamate. Under such low energy conditions the cell is not able to takeglutamate back into the cell. Initial glutamate release stimulatesfurther release of glutamate which results in an extracellular glutamateaccumulation and a cascade of neurotoxic injury.

It has been shown that the sensitivity of central neurons to hypoxia andischemia carn be reduced by either blockage of synaptic transmission orby the specific antagonism of postsynaptic glutamate receptors [see S.M. Rothman and J. W. Olney, "Glutamate and the Pathophysiology ofHypoxia - Ischemic Brain. Damage," Annals of Neurology, Vol. 19, No. 2(1986)]. Glutamate is characterized as a broad spectrum agonist havingactivity at three neuronal excitatory amino acid receptor sites. Thesereceptor sites are named after the amino acids which selectively excitethem, namely: Kainate (KA), N-methyl-D-aspartate (NMDA or NMA) andquisqualate (QUIS).

Neurons which have EAA receptors on their dendritic or somal surfacesundergo acute excitotoxic degeneration when these receptors areexcessively activated by glutamate. Thus, agents which selectively blockor antagonize the action of glutamate at the EAA synaptic receptors ofcentral neurons can prevent neurotoxic injury associated with hypoxia,anoxia, or ischemia caused by stroke, cardiac arrest or perinatalasphyxia.

It is known that compounds of various structures, suchaminophosphonovalerate derivatives and piperidine dicarboxylatederivatives, may act as competitive antagonists at the NMDA receptor andalso block the increase in cyclic GMP levels due to the presence ofexcitatory amino acids [P. L. Wood et al, Neuropharm., 21, 1235-1238(1982)].

Certain piperidineethanol derivatives, such as ifenprodil and(±)-α-(4-chlorophenyl)-4-[(4-fluorophenyl)methyl]-1-piperidineethanol,which are known anti-ischemic agents, have been found to benon-competitive NMDA receptor antagonists which also block the increaseof cyclic GMP levels due to the presence of excitatory amino acids [C.Carter et al, J. Pharm Exp. Ther., 247 (3), 1222-1232 (1988)].

Ethanoanthracene-type compounds have been identified for otherpharmaceutical uses. For example tricyclic oligoamine compounds, such asN,N'-bis-(4-phenylbutyl)-9,10-dihydro-9,10-ethanoanthracene-11,12bis-methylamine,has been mentioned for use as inhibitors of platelet aggregation (K.Rehse et al, Arch. Pharm. (Neinheim), 320, 829-836 (1987)]. A class ofdihydro-9,10-ethano-9,10-anthracene compounds, including9,10-dihydro-1,2-(1-pyrrolidinylmethyl)-9,10-ethanoanthracen-11-one,have been evaluated for analgesic activity [S. Lecolier, Chim. Ther., 3,34-38 (1968)]. Certain 9,10-dihydro-9,10-ethanoanthracene derivatives,includingN-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]-N,N',N'-trimethylethylenediamine,4-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]-1-methylpiperizine and1-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]piperidine have beendescribed as having anticholinergic, antihistaminic, local anesthetic orhypotensive properties [J. R. Boissier et al, J. Med. Chem., 10, 86-91(1967)]. U.S. Pat. No. 3,422,104 describes9,10-dihydro-9,10-ethanoanthracene compounds, includingN-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]dimethylamine,4-[(9,10-dihydro-9,10-ethanoanthracenyl)-methyl]-1(2-hydroxyethyl)piperizineand 1-[(9,10-dihydro-9,10-ethanoanthracenyl)-ethyl]piperidine for use asa spasmolytic or in treatment of depression. Swiss Pat. No. 482,642describes certain 11-aminoalkyl-9,10-dihydro-9,10-ethanoanthracenes,including N-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]methylamine,4-methylpiperazide of 9,10-dihydro-9,10-ethanoanthracene-11-carboxylicacid and 1-[(9,10-dihydro-9,10-ethanoanthracenyl)ethyl]piperidine asanesthetics.

DESCRIPTION OF THE INVENTION

Treatment of a mammal afflicted by or susceptible to a neurodegenerativedisease or neurotoxic injury is provided by administering to the mammala therapeutically-effective amount of one or more compounds selectedfrom a class of bridged tricyclic amine derivatives defined by FormulaI: ##STR2## wherein A is a group selected from ##STR3## wherein each ofR¹ and R² is independently selected from hydrido, alkyl, cycloalkyl,cycloalkylalkyl, aralkyl, aryl, hydroxyalkyl, alkoxyalkyl and halo;wherein R¹ and R² may be taken together to form oxo; wherein each of R³through R⁷ is independently selected from hydrido, alkyl, hydroxy,cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, alkoxyalkyl,aryloxy, aralkoxy, hydroxyalkyl, halo and haloalkyl; wherein R⁴ and R⁵may be taken together to form oxo; wherein n is a number selected fromzero to five, inclusive; wherein each X is independently one or moregroups selected from hydrido, hydroxy, alkyl, cycloalkyl,cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, alkoxyalkyl,haloalkyl, hydroxyalkyl, halo, cyano, amino, monoalkylamino,dialkylamino, nitro, carboxy, carboxyalkyl and alkanoyl; wherein each ofR⁸ and R⁹ is independently selected from hydrido, alkyl, cycloalkyl,cycloalkylalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, aralkyl, aryl,alkoxyalkyl and hydroxyalkyl; wherein each of R¹⁰ through R¹³ isindependently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl,aralkyl, aryl, alkoxyalkyl, hydroxyalkyl and halo; wherein R¹⁰ and R¹¹may be taken together to form oxo; wherein R¹² and R¹³ may be takentogether to form oxo; wherein each of p and q is a number selected fromone to four, inclusive; wherein Z is selected from O, S, >N--R¹⁸, >SOand >SO₂ ; wherein R¹⁸ may be selected from hydrido, alkyl, cycloalkyl,cycloalkylalkyl, aryl, aralkyl, heteroaryl, alkoxyalkyl, hydroxyalkyl,alkanoyl, aralkanoyl, aroyl, aminoalkyl, monoalkylaminoalkyl anddialkylaminoalkyl; wherein R¹⁸ together with one of R¹⁰ through R¹³ mayform a fused heterocyclic ring containing five to about eight ringmembers; wherein each of R¹⁴ through R¹⁷ is independently selected fromhydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl,hydroxyalkyl and halo; wherein R¹⁴ and R¹⁵ may be taken together to formoxo; wherein R¹⁶ and R¹⁷ may be taken together to form oxo; wherein eachof r and t is a number independently selected from one to four,inclusive; wherein G is selected to form a heterocyclic ring containingone or more groups independently selected from ##STR4## wherein each ofR¹⁹ through R²² is independently selected from hydrido, hydroxy, alkyl,cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy,alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino,monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl; or apharmaceutically-acceptable salt thereof.

A first family of preferred compounds within Formula I consists ofcompounds of Formula II ##STR5## wherein each of R¹ and R² isindependently selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl,aralkyl, aryl, hydroxyalkyl, alkoxyalkyl and halo; wherein R¹ and R² maybe taken together to form oxo; wherein each of R³ through R⁷ isindependently selected from hydrido, alkyl, hydroxy, cycloalkyl,cycloalkylalkyl, aralkyl, aryl, alkoxy, alkoxyalkyl, aryloxy, aralkoxy,hydroxyalkyl, halo and haloalkyl; wherein R⁴ and R⁵ may be takentogether to form oxo; wherein n is a number selected from zero to five,inclusive; wherein each X is independently one or more groups selectedfrom hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl,aryl, alkoxy, aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl,halo, cyano, amino, monoalkylamino, dialkylamino, nitro, carboxy,carboxyalkyl and alkanoyl; wherein each of R⁸ and R⁹ is independentlyselected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl,monoalkylaminoalkyl, dialkylaminoalkyl, aralkyl, aryl, alkoxyalkyl, andhydroxyalkyl; or a pharmaceutically-acceptable salt thereof.

A preferred family of compounds within Formula II consists of compoundswherein each of R¹ and R² is independently selected from hydrido, alkyl,cycloalkyl, cycloalkylalkyl, aralkyl, aryl, hydroxyalkyl, alkoxyalkyland halo; wherein R¹ and R² may be taken together to form oxo; whereineach of R³ through R⁷ is independently selected from hydrido, alkyl,hydroxy, cycloalkyl, cycloalkylalkyl, phenalkyl, phenyl, alkoxy,alkoxyalkyl, phenoxy, phenalkoxy, hydroxyalkyl, halo and haloalkyl;wherein R⁴ and R⁵ may be taken together to form oxo; wherein n is anumber from zero to five, inclusive; wherein each X is independently oneor more groups selected from hydrido, hydroxy, alkyl, cycloalkyl,cycloalkylalkyl, phenalkyl, phenyl, alkoxy, phenalkoxy, phenoxy,alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino,monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl;wherein each of R⁸ and R⁹ is independently selected from hydrido, alkyl,cycloalkyl, cycloalkylalkyl, monoalkylaminoalkyl, dialkylaminoalkyl,phenalkyl, phenyl, alkoxyalkyl and hydroxyalkyl; or apharmaceutically-acceptable salt thereof.

A more preferred family of compounds within Formula II consists ofcompounds wherein each of R¹ and R² is independently selected fromhydrido, loweralkyl, phenylloweralkyl, phenyl and loweralkoxyloweralkyl;wherein R¹ and R² may be taken together to form oxo; wherein each of R³through R⁷ is independently selected from hydrido, loweralkyl, hydroxy,cycloalkyl of three to eight carbon atoms, cycloalkylalkyl of four toeight carbon atoms, phenylloweralkyl, phenyl, loweralkoxy,loweralkoxyloweralkyl, phenoxy, phenalkoxy, hydroxyloweralkyl, halo andhaloloweralkyl; wherein R⁴ and R⁵ may be taken together to form oxo;wherein n is a number selected from zero to five, inclusive; whereineach X is independently one or more groups selected from hydrido,hydroxy, loweralkyl, cycloalkyl of three to about eight carbon atoms,cycloalkylalkyl of four to about eight carbon atoms, phenylloweralkyl,phenyl, loweralkoxy, phenoxy, loweralkoxyloweralkyl, haloloweralkyl,hydroxyloweralkyl, halo, carboxy, carboxyloweralkyl and loweralkanoyl;wherein each of R⁸ and R⁹ is independently selected from hydrido,loweralkyl, cycloalkyl of three to about eight carbon atoms,cycloalkylalkyl of four to about eight carbon atoms, phenylloweralkyl,phenyl, monoalkylaminoalkyl, dialkylaminoalkyl, loweralkoxyloweralkyland hydroxyloweralkyl; or a pharmaceutically-acceptable salt thereof.

A highly preferred family of compounds within Formula II consists ofcompounds wherein each of R¹ and R² is independently selected fromhydrido, loweralkyl, benzyl and phenyl; wherein R¹ and R² may be takentogether to form oxo; wherein n is selected from zero to two, inclusive;wherein each of R³ through R⁷ is independently selected from hydrido,loweralkyl, hydroxy, benzyl, phenyl, loweralkoxy, phenoxy, benzyloxy,halo and haloloweralkyl; wherein each X is independently one or moregroups selected from hydrido, hydroxy, loweralkyl, benzyl, phenyl,loweralkoxy, phenoxy, haloloweralkyl, halo and loweralkanoyl; whereineach of R⁸ and R⁹ is independently selected from hydrido, loweralkyl,benzyl, phenyl, monoloweralkylaminoloweralkyl,diloweralkylaminoloweralkyl, loweralkoxyloweralkyl andhydroxyloweralkyl; or a pharmaceutically-acceptable salt thereof.

A more highly preferred family of compounds within Formula II consistsof compounds wherein each of R¹ and R² is independently hydrido ormethyl; wherein R¹ and R² may be taken together to form oxo; whereineach of R³ through R⁷ is independently selected from hydrido, methyl,ethyl, hydroxy, methoxy, halo and trihalomethyl; wherein each of R⁸ andR⁹ may be independently selected from hydrido, methyl, ethyl,hydroxymethyl, hydroxyethyl, dimethylaminoethyl and diethylaminoethyl;wherein n is one or two; and wherein each X is independently one or moregroups selected from hydrido, methyl, ethyl, hydroxy, methoxy,trihalomethyl and halo; or a pharmaceutically-acceptable salt thereof.

Specific compounds of most interest within Formula II areN-diethylaminoethyl-9,10-dihydro-9,10-ethanoanthracene-11-carboxamide;N-diethylaminoethyl-9,10-dibromo-9,10-dihydro-9,10-ethanoanthracene-11-methyl-11-carboxamide;andN-(2-hydroxyethyl)-N-methyl-9,10-dihydro-9,10-ethanoanthracenylmethylamine,of which the last compound is of highest interest.

A second family of preferred compounds within Formula I consists ofcompounds of Formula III: ##STR6## wherein each of R¹, R² and R¹⁰through R¹³ is independently selected from hydrido, alkyl, cycloalkyl,cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, hydroxyalkyl and halo;wherein R¹⁰ and R¹¹ may be taken together to form oxo; wherein R¹² andR¹³ may be taken together to form oxo; wherein R¹ and R² may be takentogether to form oxo; wherein each of R³ through R⁷ is independentlyselected from hydrido, alkyl, hydroxy, cycloalkyl, cycloalkylalkyl,aralkyl, aryl, alkoxy, alkoxyalkyl, aryloxy, aralkoxy, hydroxyalkyl,halo and haloalkyl; wherein R⁴ and R⁵ may be taken together to form oxo;wherein n is a number selected from zero to five, inclusive; whereineach of p and q is a number selected from one to four, inclusive;wherein Z is selected from O, S, >N--R¹⁸, >SO and >SO₂ ; wherein R¹⁸ maybe selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heteroaryl, alkoxyalkyl, hydroxyalkyl, alkanoyl, aralkanoyl,aroyl, aminoalkyl, monoalkylaminoalkyl and dialkylaminoalkyl; whereinR¹⁸ together with one of R.sup. 10 through R¹³ may form a fusedheterocyclic ring containing five to about eight ring members; whereineach X is independently one or more groups selected from hydrido,hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy,aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano,amino, monoalkylamino, dialkylamino, nitro, carboxy, carboxyalkyl andalkanoyl; or a pharmaceutically-acceptable salt thereof.

A preferred family of compounds within Formula III consists of compoundswherein each of R¹, R² and R¹⁰ through R¹³ is independently selectedfrom hydrido, alkyl, cycloalkyl, cycloalkylalkyl, phenalkyl, phenyl,alkoxyalkyl, hydroxyalkyl and halo; wherein R¹ and R² may be takentogether to form oxo; wherein each of R³ through R⁷ is independentlyselected from hydrido, alkyl, hydroxy, cycloalkyl, cycloalkylalkyl,phenalkyl, phenyl, alkoxy, alkoxyalkyl, phenoxy, phenalkoxy,hydroxyalkyl, halo and haloalkyl; wherein R⁴ and R⁵ may be takentogether to form oxo; wherein n is a number from zero to five,inclusive; wherein each of p and q is a number selected from one tofour, inclusive; wherein Z is selected from O, S and N--R¹⁸ ; whereinR¹⁸ may be selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl,phenyl, phenalkyl, heteroaryl, alkoxyalkyl, hydroxyalkyl, alkanoyl,phenalkanoyl, aroyl, aminoalkyl, monoalkylaminoalkyl anddialkylaminoalkyl; wherein R¹⁸ together with one of R¹⁰ through R¹³ forma fused heterocyclic ring containing five to about eight ring members;wherein each X is independently one or more groups selected fromhydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, phenalkyl, phenyl,alkoxy, phenalkoxy, phenoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo,cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl andalkanoyl; or a pharmaceutically-acceptable salt thereof.

A more preferred family of compounds within Formula III consists ofcompounds wherein each of R¹⁰ through R¹³ is independently selected fromhydrido, loweralkyl, cycloalkyl of three to about eight carbon atoms,cycloalkylalkyl of four to about eight carbon atoms, phenylloweralkyl,phenyl, loweralkoxyloweralkyl, hydroxyloweralkyl and halo; wherein eachof R¹ and R² is independently selected from hydrido, loweralkyl,phenylloweralkyl, phenyl and loweralkoxyloweralkyl; wherein R¹ and R²may be taken together to form oxo; wherein each of R³ through R⁷ isindependently selected from hydrido, loweralkyl, hydroxy, cycloalkyl ofthree to eight carbon atoms, cycloalkylalkyl of four to eight carbonatoms, phenylloweralkyl, phenyl, loweralkoxy, loweralkoxyloweralkyl,phenoxy, phenalkoxy, hydroxyloweralkyl, halo and haloloweralkyl; whereinR⁴ and R⁵ may be taken together to form oxo; wherein n is a numberselected from zero to five, inclusive; wherein each of p and q is two orthree; wherein Z is selected from O, S, >N--R¹⁸ ; wherein R¹⁸ may beselected from hydrido, loweralkyl, cycloalkyl of three to about eightcarbon atoms, cycloalkylalkyl of four to about eight carbon atoms,phenyl, phenylloweralkyl, loweralkoxyloweralkyl, hydroxyloweralkyl,loweralkanoyl and heteroaryl selected from saturated, partiallyunsaturated and fully unsaturated heterocyclic rings containing five toseven ring members of which one or two ring members are selected fromoxygen atom and nitrogen atom; wherein R¹⁸ together with one of R¹⁰through R¹³ may form a fused heterocyclic ring containing five or sixring members; wherein each X is independently one or more groupsselected from hydrido, hydroxy, loweralkyl, cycloalkyl of three to abouteight carbon atoms, cycloalkylalkyl of four to about eight carbon atoms,phenylloweralkyl, phenyl, loweralkoxy, phenoxy, loweralkoxyloweralkyl,haloloweralkyl, hydroxyloweralkyl, halo, carboxy, carboxyloweralkyl andloweralkanoyl; or a pharmaceutically-acceptable salt thereof.

A highly preferred family of compounds within Formula III consists ofcompounds of Formula IV: ##STR7## wherein each of R¹ and R² isindependently selected from hydrido, loweralkyl, benzyl and phenyl;wherein R¹ and R² may be taken together to form oxo; wherein each of R³through R⁷ is independently selected from hydrido, loweralkyl, hydroxy,benzyl, phenyl, benzyl, loweralkoxy, phenoxy, benzyloxy, halo andhaloloweralkyl; wherein R¹⁸ may be selected from hydrido, loweralkyl,cycloalkyl of five or six carbon atoms, cycloalkylalkyl of six or sevencarbon atoms, phenyl, hydroxyloweralkyl, and heteroaryl selected fromsaturated or fully unsaturated heterocyclic rings containing five toseven ring members of which one or two ring members are nitrogen atom;wherein each X is independently one or more groups selected fromhydrido, hydroxy, loweralkyl, benzyl, phenyl, loweralkoxy, phenoxy,haloloweralkyl, halo, and loweralkanoyl; and wherein each of R²³ throughR³⁰ is independently selected from hydrido, loweralkyl, benzyl, phenyland halo; wherein R¹⁸ together with one of R²³, R²⁴, R²⁹ or R³⁰ may forma fused heterocyclic ring containing five or six ring members; or apharmaceutically-acceptable salt thereof.

A more highly preferred family of compounds consists of compounds withinFormula IV wherein each of R¹ and R² is independently hydrido or methyl;wherein R¹ and R² may be taken together to form oxo; wherein each of R³through R⁷ is independently selected from hydrido, methyl, ethyl,hydroxy, methoxy, halo and trihalomethyl; wherein R¹⁸ is selected fromhydrido, methyl, ethyl, hydroxyethyl, benzyl, pyridyl and pyrimidyl;wherein each of R²³ through R³⁰ is independently selected from hydrido,methyl, ethyl and trihalomethyl; wherein R¹⁸ together with one of R²³,R²⁴, R²⁹ or R³⁰ may form a fused heterocyclic ring containing five orsix ring members; and wherein each X is independently one or more groupsselected from hydrido, methyl, ethyl, hydroxy, methoxy, trihalomethyland halo; or a pharmaceutically-acceptable salt thereof.

Specific compounds of most interest within Formula IV are4-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]-1-methylpiperazine;4-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]-1-(2-hydroxyethyl)-piperazine;4-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]-1-(2-pyrimidyl)piperazine;4-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl-1,4-diazabicyclo[4.3.0]-nonane;4-[(9,10-dihydro-9,10-ethanoanthracenyl)carbonyl-]1-methylpiperazine;and 4-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]-1-benzylpiperazine.

Of highest interest are the compounds4-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]-1-(2-pyrimidyl)piperazine;4-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]-1,4-diazabicyclo[4.3.0]nonane;and 4-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]-1-benzylpiperazine.

A third family of preferred compounds within Formula I consists ofcompounds of Formula V: ##STR8## wherein each of R¹, R² and R¹⁴ throughR¹⁷ is independently selected from hydrido, alkyl, cycloalkyl,cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, hydroxyalkyl and halo;wherein R¹ and R² may be taken together to form oxo wherein R¹⁴ and R¹⁵may be taken together to form oxo; wherein R¹⁶ and R¹⁷ may be takentogether to form oxo; wherein each of R³ through R⁷ is independentlyselected from hydrido, alkyl, hydroxy, cycloalkyl, cycloalkylalkyl,aralkyl, aryl, alkoxy, alkoxyalkyl, aryloxy, aralkoxy, hydroxyalkyl,halo and haloalkyl; herein R⁴ and R⁵ may be taken together to form oxo;wherein n is a number selected from zero to five, inclusive; whereineach of r and t is a number independently selected from one to four;wherein each X is independently one or more groups selected fromhydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl,alkoxy, aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo,cyano, amino, monoalkylamino, dialkylamino, nitro, carboxy, carboxyalkyland alkanoyl; wherein G is selected to form a heterocyclic ringcontaining one or more groups independently selected from ##STR9##wherein each of R¹⁹ through R²² is independently selected from hydrido,hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy,aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano,amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl;or a pharmaceuticallyacceptable salt thereof.

A preferred family of compounds within Formula V consists of compoundswherein each of R¹, R² and R¹⁴ through R¹⁷ is independently selectedfrom hydrido, alkyl, cycloalkyl, cycloalkylalkyl, phenalkyl, phenyl,alkoxyalkyl, hydroxyalkyl and halo; wherein R¹ and R² may be takentogether to form oxo; wherein each of R³ through R⁷ is independentlyselected from hydrido, alkyl, hydroxy, cycloalkyl, cycloalkylalkyl,phenalkyl, phenyl, alkoxy, alkoxyalkyl, phenoxy, phenalkoxyhydroxyalkyl, halo and haloalkyl; wherein R⁴ and R⁵ may be takentogether to form oxo; wherein n is a number from zero to five,inclusive; wherein each of r and t is a number independently selectedfrom one to four, inclusive; wherein each X is independently one or moregroups selected from hydrido, hydroxy, alkyl, cycloalkyl,cycloalkylalkyl, phenalkyl, phenyl, alkoxy, phenalkoxy, phenoxy,alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino,monoalkylamino, dialkylamino, carboxy, carboxyalkyl and alkanoyl;wherein G is selected to form a heterocyclic ring containing one or moregroups independently selected from ##STR10## wherein each of R¹⁹ throughR²² is independently selected from hydrido, hydroxy, alkyl, cycloalkyl,cycloalkylalkyl, phenalkyl, phenyl, alkoxy, phenoxy, phenalkoxy,alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, amino, monoalkylamino,dialkylamino, and alkanoyl; or a pharmaceutically-acceptable saltthereof.

A more preferred family of compounds within Formula V consists ofcompounds wherein each of R¹⁴ through R¹⁷ is independently selected fromhydrido, loweralkyl, cycloalkyl of three to about eight carbon atoms,cycloalkylalkyl of four to about eight carbon atoms, phenylloweralkyl,phenyl, loweralkoxyloweralkyl, hydroxyloweralkyl and halo; wherein eachof R¹ and R² is independently selected from hydrido, loweralkyl,phenylloweralkyl, phenyl and loweralkoxyloweralkyl; wherein R¹ and R²may be taken together to form oxo; wherein each of R³ through R⁷ isindependently selected from hydrido, loweralkyl, hydroxy, cycloalkyl ofthree to eight carbon atoms, cycloalkylalkyl of four to eight carbonatoms, phenylloweralkyl, phenyl, loweralkoxy, loweralkoxyloweralkyl,phenoxy, phenalkoxy, hydroxyloweralkyl, halo and haloloweralkyl; whereinR⁴ and R⁵ may be taken together to form oxo; wherein n is a numberselected from zero to five, inclusive; wherein each of r and t isindependently two or three; wherein each X is independently one or moregroups selected from hydrido, hydroxy, loweralkyl, cycloalkyl of threeto about eight carbon atoms, cycloalkylalkyl of four to about eightcarbon atoms, phenylloweralkyl, phenyl, loweralkoxy, phenoxy,loweralkoxyloweralkyl, haloloweralkyl, hydroxyloweralkyl, halo, carboxy,carboxyloweralkyl and loweralkanoyl; wherein G is selected to form aheterocyclic ring containing one or more groups independently selectedfrom ##STR11## wherein each of R¹⁹ through R²² is independently selectedfrom hydrido, hydroxy, loweralkyl, cycloalkyl of three to eight carbonatoms, cycloalkylalkyl of four to eight carbon atoms, phenyl,phenylloweralkyl, alkoxy, phenoxy, phenylloweralkoxy, alkoxyalkyl,haloalkyl, hydroxyalkyl, halo, amino, monoalkylamino, dialkylamino andalkanoyl; or a pharmaceutically-acceptable salt thereof.

A highly preferred family of compounds within Formula V consists ofcompounds of Formula VI: ##STR12## wherein each of R¹ and R² isindependently selected from hydrido, loweralkyl, benzyl and phenyl;wherein each of R³ through R⁷ is independently selected from hydrido,loweralkyl, hydroxy, benzyl, phenyl, benzyl, loweralkoxy, phenoxy,benzyloxy, halo and haloloweralkyl; wherein each X is independently oneor more groups selected from hydrido, hydroxy, loweralkyl, benzyl,phenyl, loweralkoxy, phenoxy, haloloweralkyl, halo, and loweralkanoyl;and wherein each of R³¹ through R⁴⁰ is independently selected fromhydrido, loweralkyl, benzyl, phenyl and halo; or apharmaceutically-acceptable salt thereof.

A more highly preferred family of compounds consists of compounds withinFormula VI wherein each of R¹ and R² is independently hydrido or methyl;wherein each of R³ through R⁷ is independently selected from hydrido,methyl, ethyl, hydroxy, methoxy, halo and trihalomethyl; wherein each ofR³¹ through R⁴⁰ is independently selected from hydrido, methyl, ethyl,benzyl and phenyl; and wherein each X is independently one or moregroups selected from hydrido, methyl, ethyl, hydroxy, methoxy,trihalomethyl and halo.

Specific compounds of most interest within Formula VI are compound isselected from4-benzyl-1-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]piperidine;1-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]-4-phenylpiperidine; and1-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]piperidine. Of highestinterest are the compounds4-benzyl-1-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]piperidine; and1-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl-4-phenylpiperidine.

The compounds of Formula I through Formula III would be particularlyuseful to treat patients having neurodegenerative disorders for treatingneurotoxic injury.

The phrase "therapeutically-effective amount" means that amount of oneor more compounds of Formula I which provides a therapeutic benefit intreatment or management of neurotoxic injury resulting from a CNSdisorder or traumatic event or in treatment or management of aneurodegenerative disease. Examples of traumatic events which may resultin neurotoxic injury are hypoxia, anoxia and ischemia associated withperinatal asphyxia, cardiac arrest or stroke. In treatment of suchtraumatic-event-related cases, a "therapeutically-effective amount" of acompound of Formula I would be an antineurotoxic or an antiexcitotoxicamount of the compound which is effective to reduce or prevent suchneurotoxic injury by inhibiting, for example, excessive amounts ofexcitotoxin from being generated near or attaching to excitatory aminoacid receptors. In cases of treatment of a neurodegenerative disease,the amount of a "therapeutically-effective amount" of a compound ofFormula I would be that amount effective to reduce or preventneurodegeneration arising from or causing CNS disorders such asconvulsions and epilepsy.

The term "hydrido" denotes a single hydrogen atom (H) which may beattached, for example, to an oxygen atom to form an hydroxyl group.Where the term "alkyl" is used, either alone or within other terms suchas "haloalkyl", "aralkyl" and "hydroxyalkyl", the term "alkyl" embraceslinear or branched radicals having one to about ten carbon atoms unlessotherwise specifically described. Preferred alkyl radicals are "loweralkyl" radicals having one to about five carbon atoms. The term"cycloalkyl" embraces radicals having three to ten carbon atoms, such ascyclopropyl, cyclobutyl, cyclohexyl and cycloheptyl. An example of"cycloalkylalkyl" is cyclohexylmethyl. The term "haloalkyl" embracesradicals wherein any one or more of the carbon atoms is substituted withone or more halo groups, preferably selected from bromo, chloro andfluoro. Specifically embraced by the term "haloalkyl" are monohaloalkyl,dihaloalkyl and polyhaloalkyl groups. A monohaloalkyl group, forexample, may have either a bromo, a chloro, or a fluoro atom within thegroup. Dihaloalkyl and polyhaloalkyl groups may be substituted with twoor more of the same halo groups, or may have a combination of differenthalo groups. Examples of a dihaloalkyl group are dibromomethyl,dichloromethyl and bromochloromethyl. Examples of a polyhaloalkyl aretrifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl and2,2,3,3-tetrafluoropropyl groups. The term "alkoxy" embraces linear orbranched oxy-containing radicals having an alkyl portion of one to aboutten carbon atoms, such as methoxy, ethoxy, isopropoxy and butoxy. Anexample of "cycloalkyloxy" is cyclohexyloxy. An example of "alkoxyalkyl"is methoxymethyl. An example of "aralkyloxy" is benzyloxy. The term"alkylthio" embraces radicals containing a linear or branched alkylgroup, of one to about ten carbon atoms attached to a divalent sulfuratom, such as a methythio group. The term "aryl" embraces aromaticradicals such as phenyl, naphthyl and biphenyl. The term "aralkyl"embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl,triphenylmethyl, phenylethyl, phenylbutyl and diphenylethyl. The terms"benzyl" and "phenylmethyl" are interchangeable. The terms "aryloxy" and"arylthio" denote radical respectively, aryl groups having an oxygen orsulfur atom through which the radical is attached to a nucleus, examplesof which are phenoxy and phenylthio. The terms "sulfinyl" and"sulfonyl", whether used alone or linked to other terms, denotesrespectively divalent radicals >SO and >SO₂. The terms "monoalkylamino"and "dialkylamino" denote amino groups which have been substituted,respectively, with one alkyl radical and with two alkyl radicals. Theterm "acyl" whether used alone, or within a term such as acyloxy,denotes a radical provided by the residue after removal of hydroxyl froman organic acid, examples of such radical being acetyl and benzoyl. Theterm "heteroaryl" embraces aromatic ring systems containing one or twohetero atoms selected from oxygen, nitrogen and sulfur in a ring systemhaving five or six ring members, examples of which are thienyl, furanyl,pyridinyl, thiazolyl, pyrimidyl and isoxazolyl. The phrase, as usedabove, "R¹⁸ together with one of R²³, R²⁴, R²⁹ and R³⁰ may form a fusedheterocyclic ring containing five or six members", is intended toembrace a bicyclic fused heterocyclic ring system which includes bothhetero atoms contained in Formula III and Formula IV, which ring systemmay be further substituted as described herein. An example of suchbicyclic fused ring system is shown as Compound No. 4, herein.

Within this class of compounds of the invention are the pharmaceuticallyacceptable salts of the compounds of Formula I, including acid additionsalts and base addition salts. The term "pharmaceutically-acceptablesalts" embraces salts commonly used to form alkali metal salts and toform addition salts of free acids or free bases. The nature of the saltis not critical, provided that it is pharmaceutically-acceptable.Suitable pharmaceutically-acceptable acid addition salts of compounds ofFormula I may be prepared from an inorganic acid or from an organicacid. Examples of such inorganic acids are hydrochloric, hydrobromic,hydroiodic, nitric, carbonic, sulfuric and phosphoric acid. Appropriateorganic acids may be selected from aliphatic, cycloaliphatic, aromatic,araliphatic, heterocyclic, carboxylic and sulfonic classes of organicacids, example of which are formic, acetic, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, p-hydroxybenzoic, salicyclic, phenylacetic, mandelic,embonic (pamoic), methansulfonic, ethanesulfonic,2-hydroxyethanesulfonic, pantothenic, benzenesulfonic, toluenesulfonic,sulfanilic, mesylic, cyclohexylaminosulfonic, stearic, algenic,β-hydroxybutyric, malonic, galactaric and galacturonic acid. Suitablepharmaceutically-acceptable base addition salts of compounds of FormulaI include metallic salts made from aluminium, calcium, lithium,magnesium, potassium, sodium and zinc or organic salts made fromN,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. All ofthese salts may be prepared by conventional means from the correspondingcompound of Formula I by reacting, for example, the appropriate acid orbase with the compound of Formula I.

Compounds of general Formula I can possess one or more asymmetric carbonatoms and are thus capable of existing in the form of optical isomers aswell as in the form of racemic or non-racemic mixtures thereof. Theoptical isomers can be obtained by resolution of the racemic mixturesaccording to conventional processes, for example by formation ofdiastereoisomeric salts by treatment with an optically active acid orbase. Examples of appropriate acids are tartaric, diacetyltartaric,dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid and thenseparation of the mixture of diastereoisomers by crystallizationfollowed by liberation of the optically active bases from these salts. Adifferent process for separation of optical isomers involves the use ofa chiral chromatography column optimally chosen to maximize theseparation of the enantiomers. Still another available method involvessynthesis of covalent diastereoisomeric molecules by reacting compoundsof Formula I with an optically pure acid in an activated form or anoptically pure isocyanate. The synthesized diastereoisomers can beseparated by conventional means such as chromatography, distillation,crystallization or sublimation, and then hydrolyzed to deliver theenantiomerically pure compound. The optically active compounds ofFormula I can likewise be obtained by utilizing optically activestarting materials. These isomers may be in the form of a free acid, afree base, an ester or a salt.

General Synthetic Procedures

Compounds of Formula I may be prepared in accordance with the followinggeneric procedures, which show preparation of three different familiesof compounds containing three different amino terminal groups.

Generic Procedure I

This general procedure of Step 1 applies to preparation of all threefamilies.

Step 1(a): ##STR13## wherein X and R¹ through R⁷ are as previouslydescribed; and wherein L is halogen, tosylate, mesylate, brosylate orOH.

A process for preparing the compounds of the invention starts withanthracenes of general structure 1 where X, R⁶ and R⁷ have the valueassigned previously. The anthracene is combined with alkenes of generalstructure 2 where R¹ through R⁵ have the value assigned previously and Lis a good leaving group such as chloro, bromo, mesylate, tosylate or OH.The reaction is best achieved by mixing the reagents neat or in asolvent like benzene, toluene, or xylenes. The reaction temperature canvary from about 150° C. to about 250° C.

Step 1(b):

Alternately, compounds of general structure 3 can be prepared accordingto the following generic procedure: ##STR14## wherein X and R¹ throughR⁷ are as previously described; and wherein L is halogen, tosylate,mesylate, or brosylate. The compounds of general structure 3 thus can beprepared by mixing the alcohol 4 with a reagent such as thionylchloride, phosphorous oxychloride, triphenylphosphine dibromide,methanesulfonyl chloride and p-toluenesulfonyl chloride. The reagentscan be combined neat or in a variety of aprotic solvents such as carbontetrachloride, toluene, tetrahydrofuran, or ether. The temperature ofthe reaction may vary from room temperature to reflux of the reactionmixture.

The following Steps 2(a)(i), 2(a)(ii), 2(a)(iii), 2(b)(i), 2(b)(ii) and2(b)(iii) describes displacement reactions to make each of the threefamilies of compounds.

Step 2(a)(i): ##STR15## wherein X, L and R¹ through R⁹ are as previouslydescribed.

In the second step of the process, amines of general structure 6 areprepared by combining compounds of general structure 3 with amines ofgeneral structure 5, wherein R⁸ and R⁹ are as defined before. Thecompounds can be combined in a variety of solvents such as toluene,xylenes, dimethylformamide, hexamethylphosphoramide or ethanol. Thetemperature of the reaction can vary from room temperature to reflux ofthe reaction mixture.

Step 2(b)(i):

Alternately, amines of general structure 6 can be prepared according tothe following generic procedure: ##STR16## wherein X and R¹ through R⁹are as previously described.

In Step 2(b) of the process, amines of general structure 6 are preparedby combining an alcohol of general structure 4 with amines of generalstructure 5, where R⁸ and R⁹ are as previously defined. The compoundscan be combined in a variety of aprotic solvents such as toluene,xylenes, dimethylformamide, or hexamethylphosphoramide. The conversionrequires combining the two reagents in the solvent in the presence of astrong base such as sodium hydride and in the presence of an activatingagent such as triphenylphosphine,N-methyl-N-phenylaminotriphenylphosphonium iodide or similar reagents.The temperature of the reaction can vary from room temperature to about100° C.

Step 2(a)(ii): ##STR17## wherein p, q, X, L and R¹ through R⁷ and R¹⁰through R¹³ are as previously described.

In the second step of the process, amines of general structure 8 areprepared by combining compounds of general structure 3 with amines ofgeneral structure 7, where p, q, Z, and R¹⁰ through R¹³ are aspreviously defined. The compounds can be combined in a variety ofsolvents such as toluene, xylenes, dimetlylformamide,hexamethylphosphoramide or ethanol. The temperature of the reaction canvary from room temperature to reflux of the reaction mixture.

Step 2(b)(ii):

Alternately, amines of general structure 6 can be prepared according tothe following generic procedure: ##STR18## wherein p, q, X, Z and R¹through R⁷ and R¹⁰ through R¹³ are as previously described.

In Step 2(b) of the process, amines of general structure 8 are preparedby combining an alcohol of general structure 4 with amines of generalstructure 7, where p, q, E and R¹⁰ through R¹³ are as previouslydefined. The compounds can be combined in a variety of aprotic solventssuch as toluene, xylenes, dimethylformamide, or hexamethylphosphoramide.The conversion requires combining the two reagents in the solvent in thepresence of a strong base such as sodium hydride and in the presence ofan activating agent such as triphenylphosphine,N-methyl-N-phenylaminotriphenylphosphonium iodide or similar reagents.The temperature of the reaction can vary from room temperature to about100° C.

A preferred method for preparing compounds by Generic Procedure Iinvolves the displacement reaction of Step 2 wherein compound of FormulaIV: ##STR19## wherein each of R¹ and R² is independently selected fromhydrido, loweralkyl, benzyl and phenyl; wherein each of R³ through R⁷ isindependently selected from hydrido, loweralkyl, hydroxy, benzyl,phenyl, loweralkoxy, phenoxy, benzyloxy, halo and haloloweralkyl;wherein R¹⁸ may be selected from hydrido, loweralkyl, cycloalkyl of fiveor six carbon atoms, cycloalkylalkyl of six or seven carbon atoms,phenyl, benzyl, hydroxyloweralkyl, and heteroaryl selected fromsaturated or fully unsaturated heterocyclic rings containing five toseven ring members of which one or two ring members are nitrogen atom;wherein each X is independently one or more groups selected fromhydrido, hydroxy, loweralkyl, benzyl, phenyl, loweralkoxy, phenoxy,haloloweralkyl halo, and loweralkanoyl; and wherein each of R²³ throughR³⁰ is independently selected from hydrido, loweralkyl, benzyl, phenyland halo; wherein R¹⁸ together with one of R²³, R²⁴, R²⁹ or R³⁰ may forma fused heterocyclic ring containing five or six ring members; or apharmaceutically-acceptable salt thereof; said method comprisingreacting a compound of the formula ##STR20## wherein each of R¹ throughR⁷ and X is defined above; and wherein L is selected from halo, hydroxy,paratoluenesulfonyloxy, methylsulfonyloxy andparabromotoluenesulfonyloxy; with an amine of the formula ##STR21##wherein each of R¹⁸ and R²³ through R³⁰ is as defined above.

Step 2(a)(iii): ##STR22## wherein p, q, G, X, L and R¹ through R¹⁷ areas previously described.

In the second step of the process, amines of general structure 10 areprepared by combining compounds of general structure 3 with amines ofgeneral structure 9, where r, t, G, and R¹⁴ through R¹⁷ are aspreviously defined. The compounds can be combined in a variety ofsolvents such as toluene, xylenes, dimethylformamide,hexamethylphosphoramide or ethanol. The temperature of the reaction canvary from room temperature to reflux of the reaction mixture.

Step 2(b)(iii):

Alternately, amines of general structure 6 can be prepared according tothe following generic procedure: ##STR23## wherein r, t, G, X and R¹through R¹⁷ are as previously described.

In Step 2(b) of the process, amines of general structure 10 are preparedby combining an alcohol of general structure 4 with amines of generalstructure 9, where r, t, G and R¹⁴ through R¹⁷ are as previouslydefined. The compounds can be combined in a variety of aprotic solventssuch as toluene, xylenes, dimethylformamide, or hexamethylphosphoramide.The conversion requires combining the two reagents in the solvent in thepresence of a strong base such as sodium hydride and in the presence ofan activating agent such as triphenylphosphine,N-methyl-N-phenylaminotriphenylphosphonium iodide or similar reagents.The temperature of the reaction can vary from room temperature to about100° C.

A preferred method for preparing compounds by Generic Procedure Iinvolves the displacement reaction of Step 2 wherein compound of FormulaVI: ##STR24## wherein each of R¹ and R² is independently selected fromhydrido, loweralkyl, benzyl and phenyl; wherein each of R³ through R⁷ isindependently selected from hydrido, loweralkyl, hydroxy, benzyl,phenyl, loweralkoxy, phenoxy, benzyloxy, halo and haloloweralkyl;wherein each X is independently one or more groups selected fromhydrido, hydroxy, loweralkyl, benzyl, phenyl, loweralkoxy, phenoxy,haloloweralkyl, halo, and loweralkanoyl; and wherein each of R³¹ throughR⁴⁰ is independently selected from hydrido, loweralkyl, benzyl, phenyland halo; or a pharmaceutically-acceptable salt thereof; said methodcomprising reacting a compound of the formula ##STR25## wherein each ofR¹ through R⁷ and X is defined above; and wherein L is selected fromhalo, hydroxy, paratoluenesulfonyloxy, methylsulfonyloxy andparabromotoluenesulfonyloxy; with an amine of the formula ##STR26##wherein each of R³¹ through R⁴⁰ is as defined above.

Generic Procedure II

In this general description, preparation of all three families ofcompounds are identical for Steps 1-3, shown below: ##STR27## wherein Xand R³ through R⁷ are as defined before; and wherein Z is selected fromlower alkoxy or benzyloxy.

An alternate process that can be used to synthesize the products of theinvention starts with anthracenes of general structure l where X, R⁶ andR⁷ have the values assigned previously. The anthracene l is combinedwith acrylates of general structure ll where Z and R³ through R⁵ havethe value assigned previously. The reaction is best achieved by mixingthe reagents neat or in a solvent like benzene, toluene, or xylenes. Thereaction temperatures can vary from about 150° C. to about 250° C.

Step 2: ##STR28## wherein X and R³ through R⁷ are as defined before;wherein Z is selected from lower alkoxy or benzyloxy; wherein A isselected from a variety of bases such as sodium hydroxide, lithiumhydroxide or potassium hydroxide.

In the second step of the process, the ester 12 is hydrolyzed to theacid 13 by mixing the ester with water in the presence of a base such assodium hydroxide, lithium hydroxide or potassium hydroxide. The reactionis best achieved by mixing the reagents neat or in a solvent such asethanol or methanol. The reaction temperature can vary from about roomtemperature to reflux of the reaction mixture.

Step 3 ##STR29## wherein X and R³ through R⁷ are as defined before; andwherein L represents a good leaving group such as chloro, bromo, oracyl.

In the third step of the process, the acid 13 is converted to a compoundof the general structure 14, where L is a good leaving group such aschloro, bromo or acyl. The conversion can be best achieved by mixing theacid 13 with reagents such as thionyl chloride, phosphorous oxychloride,phosphorous tribromide, or other reagents. This conversion is bestachieved by mixing the reagents neat or in an aprotic solvent such astetrahydrofuran, methylene chloride, or ether. The temperature of thereaction can vary from room temperature to reflux of the reactionmixture.

The following steps 4(i), 4(ii), 4(iii), 5(i), 5(ii) and 5(iii) describedisplacement steps for making each of the three families of compounds:Step 4(i): ##STR30## wherein X, L, R³ through R⁷ are as defined before.

In the fourth step of the process, compounds of general structure 14 areconverted to amides of general structure 15 by reaction with amines ofgeneral structure 5, where R⁸ and R⁹ are as defined before. Thisconversion is best achieved by mixing the reagents neat or in an aproticsolvent such as tetrahydrofuran, methylene chloride, or ether. Thetemperature of the reaction can vary from 0° C. to reflux of thereaction mixture.

Step 5(i): ##STR31## wherein X, R³ through R⁹ are as defined before.

In the fifth step of the process, amides of general structure 150 areconverted to amines of general structure 6 by employing reducing agentssuch as lithium aluminum hydride, sodium borohydride, sodiumcyanoborohydride, or other reducing agents familiar to those skilled inthe art. This reduction can be accomplished in either protic or aproticsolvents, depending on the reducing agent of choice, and at temperaturesranging from room temperature to reflux of the reaction mixture.

Step 4(ii): ##STR32## wherein p, q, X, Z, L, R³ through R⁷ and R¹⁰through R¹³ are as defined before.

In the fourth step of the process, compounds of general structure 14 areconverted to amides of general structure 16 by reaction with amines ofgeneral structure 7, where p, q, Z and R¹⁰ through R¹³ are as definedbefore. This conversion is best achieved by mixing the reagents neat orin an aprotic solvent such as tetrahydrofuran, methylene chloride, orether. The temperature of the reaction can vary from 0° C. to reflux ofthe reaction mixture.

Step 5(ii): ##STR33## wherein p, q, X, L, R⁸ through R⁷ and R¹⁰ throughR¹³ are as defined before.

In the fifth step of the process, amides of general structure 16 areconverted to amines of general structure 8 by employing reducing agentssuch as lithium aluminum hydride, sodium borohydride, sodiumcyanoborohydride, or other reducing agents familiar to those skilled inthe art. This reduction can be accomplished in either protic or aproticsolvents, depending on the reducing agent of choice, and at temperaturesranging from room temperature to reflux of the reaction mixture.

Step 4(iii): ##STR34## wherein r, t, G, X, L, R³ through R⁷ and R¹⁴through R¹⁷ are as defined before.

In the fourth step of the process compounds of general structure 14 areconverted to amides of general structure 17 by reaction with amines ofgeneral structure 9, where r, t, G and R¹⁴ through R¹⁷ ; are as definedbefore. This conversion is best achieved by mixing the reagents neat orin an aprotic solvent such as tetrahydrofuran, methylene chloride, orether. The temperature of the reaction can vary from 0° C. to reflux ofthe reaction mixture.

Step 5(iii): ##STR35## wherein r, t, G, X, L, R³ through R⁷ and R¹⁴through R¹⁷ are as defined before.

In the fifth step of the process, amides of general structure 17 areconverted to amines of general structure 10 by employing reducing agentssuch as lithium aluminum hydride, sodium borohydride, sodiumcyanoborohydride, or other reducing agents familiar to those skilled inthe art. This reduction can be accomplished in either protic or aproticsolvents, depending on the reducing agent of choice, and at temperaturesranging from room temperature to reflux of the reaction mixture.

EXAMPLE I 9,10-Dihydro-9,10-ethanoanthracene-11-carboxylic Acid

Anthracene (40 gm) was combined with methyl acrylate (30 gm) in a Parrbomb and heated to 150-175° C. for 6 hours. The mixture was allowed toremain in the bomb at room temperature for 72 hours. The mixture wasdissolved in methanol (225 ml), treated with a solution of potassiumhydroxide (40 gm) in water (40 ml) and heated to reflux for 4 hours. Thesolution was cooled to room temperature and most of the solvent wasremoved on a rotary evaporator. The residue was dissolved in water (200ml), filtered through charcoal and acidified with concentratedhydrochloric acid. The resulting mixture was allowed to stand overnightand the precipitate was filtered. The white solid was dried at 80° andrecrystallized from benzene to provide the product (mp=188-189° C.).

EXAMPLE IIN-Diethylaminoethyl-9,10-dihydro-9,10-ethanoanthracene11-carboxamide(Compound No. 10)

9,10-Dihydro-9,10-ethanoanthracene-11-carboxylic acid (25 gm) wascombined with thionyl chloride (7.3 ml), benzene (150 ml) and pyridine(7.9 gm) and the resulting mixture was heated to reflux 1.5 hours. Themixture was cooled to room temperature, filtered and treated with2-diethylaminoethylamine (11.6 gm). The resulting mixture was heated toreflux for 5 hours. The solution was concentrated on a rotary evaporatorand the solid residue was suspended in ether, filtered and air dried.The product was recrystallized from ethyl acetate. Analytical data arereported in Table I.

EXAMPLE III9,10-Dibromo-9,10-Dihydro-9,10-ethanoanthracene-11-methyl-11-carboxylicacid

9,10-Dibromoanthracene (101 gm) was combined with methyl methacrylate(50 ml) and heated in a Parr bomb to 160-180° C. for 8 hours. Theresulting material was combined with methanol (500 ml), potassiumhydroxide (50 gm) and water (50 ml) and heated to reflux for 4 hours.The mixture was allowed to cool to room temperature and to standovernight. The solvent was removed on a rotary evaporator and theresidue was extracted with water. The aqueous solution was washed withether and acidified with concentrated hydrochloric acid. The precipitatewas filtered and recrystallized from xylenes to provide the product(mp=237-239° C.).

EXAMPLE IV 11-Chloromethyl-9,10-dihydro-9,10-ethanoanthracene

Anthracene (75 gm) was combined with allyl chloride (150 gm) and benzene(375 gm) in a Parr bomb and heated to 220° C. for 13 hours. The contentswere filtered and the benzene was removed on a rotary evaporator. Theresidue was recrystallized from ethanol to provide the product as awhite solid (mp=108-111° C.).

EXAMPLE VN-(2-Hydroxyethyl)-N-methyl-9,10-Dihydro-9,10-ethanoanthracenylmethylamine(Compound No. 12)

11-Chloromethyl-9,10-dihydro-9,10-ethanoanthracene (45 gm) was combinedwith 2-hydroxyethylmethylamine (45 gm) in xylene (300 ml) and themixture heated to reflux for 17 days. The mixture was cooled to roomtemperature and extracted with 1 N hydrochloric acid (3×100 ml). Thecombined acid solutions were washed with ether (100 ml), made basic withthe addition of 50% sodium hydroxide solution and the mixture extractedwith ether (3×100 ml). The combined ether solutions were dried overmagnesium sulfate and the ether removed on a rotary evaporator. Theresidue was distilled (220° C. at 7 mm Hg) to yield a colorless oil. Thematerial was dissolved in ether (200 ml) and treated with 6 Nhydrochloric acid in isopropyl alcohol (2 ml). The resulting precipitatewas filtered and washed with ether to provide the product. Analyticaldata are reported in Table I.

EXAMPLE VI 9,10-Dihydro-9,10-ethanoanthracene-11-methanol

Anthracene (45.4 gm) was combined with allyl alcohol (90.8 gm) andbenzene (260 ml) in a Parr bomb and heated to 210° C. for 12 hours. Thebenzene was removed on a rotary evaporator and the residue wasrecrystallized from n-heptane to provide the product as a white solid(mp=104-105° C.).

EXAMPLE VII 11-Bromomethyl-9,10-dihydro-9,10-ethanoanthracene

9,10-Dihydro-9,10-ethanoanthracene-11-methanol (2 gm) was combined withtriphenylphosphine dibromide (5.3 gm) in carbon tetrachloride (60 ml).The mixture was heated to reflux 1 hour, filtered, and the filtrate wasconcentrated on a rotary evaporator. The residue was boiled in n-heptane(75 ml), filtered hot, and the filtrate cooled. The white precipitatewas filtered and air dried to provide the product (mp=103-106° C.).

EXAMPLE VIII 11-Bromomethyl-9,10-dihydro-9,10-ethanoanthracene(Alternate Procedure)

9,10-Dihydro-9,10-ethanoanthracene-11-methanol (1.2 gm), imidazole (0.7gm) and chlorodiphenylphosphine (1.4 gm) were combined in toluene (80ml) and treated dropwise with bromine (1.0 gm). The mixture was stirred10 minutes, then extracted with 10% sodium hydroxide (50 ml) and water(50 ml). The toluene was removed on a rotary evaporator and the residuewas dissolved in 1:1 methylene chloride/hexane and placed on a silicagel column. The column was eluted with 1:1 methylene chloride/hexane andthe eluant removed on a rotary evaporator to give the product.

EXAMPLE IX4-(9,10-Dihydro-9,10-ethanoanthracenyl)methyl]-1-methylpiperazine(Compound No. 1).

11-Bromomethyl-9,10-dihydro-9,10-ethanoanthracene (0.51 gm),1-methylpiperazine (1.9 ml) and potassium carbonate (0.20 gm) werecombined in hexamethylphosphoramide (5 ml) in a sealed tube and heatedto 90° C. for 48 hours. The mixture was extracted between water (25 ml)and ether (50 ml). The ether solution was washed with water (25 ml),then extracted with 3.6 N sulfuric acid (3×25 ml). The combined acidsolutions were made basic with the addition of concentrated aqueousammonia and the resulting mixture was extracted with ether (3×25 ml).The combined ether solutions were dried over magnesium sulfate and theether removed on a rotary evaporator. The residue was dissolved inanhydrous ether (15 ml) and treated with 3.5% hydrochloric acid inisopropyl alcohol (0.79 ml). The resulting precipitate was filtered,washed with ether (25 ml), and air dried to give the product as a whitesolid. Analytical data are reported in Table I.

EXAMPLE X Methyl 9,10-Dihydro-9,10-ethanoanthracene-11-carboxylate

Anthracene (89.0 gm) was combined with methyl acrylate (51.5 gm) andxylenes (500 ml) in a Parr bomb and heated to 210° C. for 12 hours. Thesolvent was removed on a rotary evaporator and the residue wasrecrystallized from methanol to provide the product as a white solid(m=113-114° C.).

EXAMPLE XI4-[9,10-Dihydro-9,10-ethanoanthracenyl)carbonyl]-1-(2-pyrimidyl)piperazine

9,10-Dihydro-9,10-ethanoanthracene-11-carboxylic acid (1.0 gm) wascombined with thionyl chloride (10 ml) and heated to reflux 1 hour. Theexcess thionyl chloride was removed by distillation and the residue wasdissolved in anhydrous ether (10 ml). The acid chloride solution wasadded dropwise to a solution of 1-(2-pyrimidyl)piperazine (2 gm) inether (90 ml). The resulting mixture was stirred at room temperature for1 hour. The mixture was washed with 5% sodium bicarbonate solution (2×50ml) and water (2×50 ml) and the ether solution dried over magnesiumsulfate. The ether was removed on a rotary evaporator and the crudematerial purified using preparative centrifugally accelerated radialthin layer chromatography on silica gel using 5% ethanol in methylenechloride as the eluant to provide the product as a white foam.

EXAMPLE XII

4-[(9,10-ethanoanthracenyl)methyl]-1-(2-pyrimidyl)piperazine (CompoundNo. 3)

4-[(9,10-Dihydro-9,10-ethanoanthracenyl)carbonyl-1,2-(2-pyrimidyl)piperazine(0.85 gm) was dissolved in anhydrous tetrahydrofuran and treated withlithium aluminum hydride (0.081 gm). The mixture was heated to refluxfor 15 hours. The mixture was cooled in an ice bath and treated with 1 Nhydrochloric acid (25 ml). The resulting mixture was washed with ether(2×25 ml) and the combined ether layers extracted with additional 1 Nhydrochloric acid (25 ml). The combined acid solutions were made basicby the addition of excess 50% sodium hydroxide solution and extractedwith ether (3×35 ml). The combined ether solutions were dried overmagnesium sulfate and the ether removed on a rotary evaporator. Theresidue was dissolved in isopropyl alcohol (10 ml) and treated with 6 Nhydrochloric acid in isopropyl alcohol (3 ml). The solution was allowedto stand at room temperature for 1 hour, then it was added dropwise to200 ml ether. The resulting precipitate was filtered and recrystallizedfrom isopropanol to provide the product as a white solid. Analyticaldata are reported in Table I.

EXAMPLE XIII

4-[(9,10-Dihydro-9,10-ethanoanthracenyl)methyl]-1-benzylpiperazine(Compound No. 6).

9,10-Dihydro-9,10-ethanoanthracene-11-methanol (1.2 gm) was combinedwith dimethylformamide (5 ml) and treated with a 60% dispersion ofsodium hydride in mineral oil (200 mg). The mixture was stirred at roomtemperature for 15 minutes.

The resulting solution was then treated with a mixture of1-benzylpiperazine (1.8 gm) andN-methyl-N-phenylaminotriphenylphosphonium iodide (2.5 gm) indimethylformamide (10 ml). The reaction mixture was heated to 80° C. for24 hours. The reaction solution was cooled to room temperature, pouredinto water (75 ml), and the aqueous mixture was extracted with ether(3×50 ml). The combined ether solutions were extracted with 3.6 Nsulfuric acid (3×30 ml) and the combined acid extracts were made basicby the addition of excess concentrated aqueous ammonia. The resultingmixture was extracted with ether (3×50 ml) and the combined etherextracts were dried over magnesium sulfate. After removal of the etheron a rotary evaporator, the crude product was purified by preparativecentrifugally accelerated radial thin layer chromatography on silica gelusing 5% ethanol in methylene chloride as the eluant to provide a whitesolid. The solid was dissolved in anhydrous ether (50 ml), treated with3 N hydrochloric acid in isopropyl alcohol (1 ml), and the resultingprecipitate was filtered. The precipitate was recrystallized fromethanol to provide the product as a white solid. Analytical data arereported in Table I.

EXAMPLE XIV4-Benzyl-1-[(9,10-Dihydro-9,10-ethanoanthracenyl)methyl]piperidine(Compound No. 7).

11-Bromomethyl-9,10-dihydro-9,10-ethanoanthracene (1.2 gm),4-benzylpiperidine (7.0 gm) and potassium carbonate (0.40 gm) werecombined in hexamethylphosphoramide (8 ml) in a sealed tube and heatedto 90° C. for 48 hours. The mixture was extracted between water (50 ml)and ether (50 ml). The aqueous layer was extracted with ether (2×50 ml)and the combined ether solutions were washed with water (2×50 ml), thenextracted with 3.6 N sulfuric acid (3×50 ml). The combined acidsolutions were made basic with the addition of concentrated aqueousammonia and the resulting mixture was extracted with ether (3×50 ml).The combined ether solutions were dried over magnesium sulfate and theether and excess 4-benzylpiperidine were removed on a rotary evaporator.The residue was dissolved in methylene chloride (15 ml) and purified bypreparative centrifugally accelerated radial thin layer chromatographyon silica gel using 90:9:1 methylene chloride/ethanol/triethylamine asthe eluant. The crude product was dissolved in isopropyl alcohol (10 ml)and treated with 6 N hydrochloric acid in isopropyl alcohol (0.5 ml).The solution was added dropwise to ether (150 ml) and the resultingsolid was filtered. The solid was recrystallized from isopropyl alcoholto provide the product as a white solid. Analytical data are reported inTable I.

EXAMPLE XV 1-[(9,10-Dihydro-9,10 -ethanoanthracenyl)methyl]piperidine(Compound No. 9)

11-Chloromethyl-9,10-dihydro-9,10-ethanoanthracene (26 gm) was combinedwith piperidine (26 gm) in xylene (200 ml) and the mixture heated toreflux for two weeks. The mixture was cooled to room temperature andextracted with 1 N hydrochloric acid (3×75 ml). The combined acidsolutions were made basic with the addition of 50% sodium hydroxidesolution and the mixture extracted with ether (3×100 ml). The combinedether solutions were dried over magnesium sulfate and the ether removedon a rotary evaporator. The residue was distilled (220° C. at 7 mm Hg)to yield a white solid (mp=120° C.). The material was dissolved in ether(400 ml) and treated with 6 N hydrochloric acid in isopropyl alcohol (2ml). The resulting precipitate was filtered to provide the product.Analytical data are reported in Table I.

    TABLE I      Compound   Method of Elemental Analysis Melting Number Name Structure     Preparation Theor. Found Point               1 4-[(9,10-dihydro-9,10-ethanoanthra-cenyl)methyl]-1-methylpipe     razine.1.5HCl.0.8H.sub.2      O     ##STR36##      VI, VII, IXor X, I, XI,XII CHN 68.24 7.57 7.23 68.25 7.53      7.11 236-241° C.      2 4-[(9,10-dihydro-9,10-ethanoanthra-cenyl)methyl]-1-(2-hydroxyethyl)-pi     perazine.1.9HCl.0.6H.sub.2      O     ##STR37##      VI, VII, IX CHN 64.13 7.30 6.50 64.13 7.29 6.50 282-286°  C.  3     4-[(9,10-dihydro-9,10-ethanoanthra-cenyl)methyl]-1-(2-pyrimidyl)piper-azi     ne.2HCl.0.9H.sub.2      O     ##STR38##      X, XII CHN 63.58 6.3611.80 63.66 6.3611.27 276-279° C.  4     4-[(9,10-dihydro-9,10-ethanoanthra-cenyl)methyl]-1,4-diazabicyclo[4.3.0]-n     onane.1.9HCl.1.4H.sub.2      O     ##STR39##      X, XII CHN 65.58 7.51 6.37 65.59 7.35 6.21 213-216° C.  5     4-[(9,10-dihydro-9,10-ethanoanthra-cenyl)carbonyl]-1-methylpiperazine.0.3     EtOH      ##STR40##      X, XI CHN 78.25 7.54 8.05 78.36 7.38 7.58 73-76° C.      6 4-[(9,10-dihydro-9,10-ethanoanthra-cenyl)methyl]-1-benzylpiperazine.2H     Cl.0.9H.sub.2      O     ##STR41##      XIII CHN 71.27 6.94 5.94 71.25 6.98 5.89 254-256° C.      7 4-benzyl-1-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]piperidine      ##STR42##      VI, VII, XIV CHN 88.50 7.94 3.56 88.30 8.14 3.50 136-137° C.  8     1-[(9,10-dihydro-9,10-ethanoanthra-cenyl)methyl]-4-phenylpiperidine      ##STR43##      VI, VII, XIV CHN 88.61 7.70 3.69 88.23 7.96 3.52 108-110° C.  9     1-[(9,10-dihydro-9,10-ethanoanthra-cenyl)methyl]piperidine.HCl.0.3H.sub.2      O     ##STR44##      IV, XV CHN 76.92 7.79 4.08 76.92 7.79 3.99 245-250° C.  10     N-diethylaminoethyl-9,10-dihydro-9,10-ethanoanthracene-11-carbox-amide.HC     l      ##STR45##      I, II CHN 51.76 5.33 6.30 51.77 5.25 6.37 136-137.5° C.  11     N-diethylaminoethyl-9,10-dibromo-9,10-dihydro-9,10-ethanoanthracene-11-me     thyl-11-carboxamide.HCl      ##STR46##      III, II CHCl 51.77 5.25 6.37 51.76 5.33 6.30 170-172° C.  12     N-(2-hydroxyethyl)-N-methyl-9,10-dihydro-9,10-ethanoanthracenyl-methylami     ne.HCl.H.sub.2      O     ##STR47##      IV, V CHN 72.82 7.33 4.25 72.72 7.16 4.12 203-204°      C.

Assay for Effect on cGMP

Male Swiss-Webster mice (17-24 g) were injected intracisternally(i.c.t.) with glycine agonists 10 minutes prior to sacrifice by focussedmicrowave irradiation. Compounds of the invention were co-injectedintracisternally with the agonist. For intracisternal injections, allagonists were dissolved in HCl and diluted with isotonic saline prior toadjustment of the pH to between 6 and 7 with NaOH. The compounds of theinvention were dissolved in isotonic saline and all compounds wereadministered in a volume of 5 μl. The agonist doses were obtained bymaking serial dilutions of a concentrated solution of drug untilintracisternal injections of 5 μl resulted in no more than 10% mortalityduring the first 15 minutes after injection.

Hydrochloric acid in extracts of the cerebellum were freeze-dried forassay of cGMP with a commercial RIA kit (NEN). Protein determinations(Lowery) and statistics (Dunett's t-test) were performed as describedpreviously [P. L. Wood et al., Neurochem., 19, 975-982 (1980)]. Groupsconsisted of 7-10 mice. Results are reported in Table II.

                  TABLE II                                                        ______________________________________                                                         Cerebellar cGMP                                              Compound         (pmol/mg protein + SEM)                                      ______________________________________                                        Saline           3.09 ± 0.48                                               D-Serine (200 μg)                                                                           17.2 ± 3.52                                               Compound No. 1 (25 μg)                                                                      3.8 ± 1.0                                                 D-Serine (200 μg) +                                                                          5.1 ± 0.93                                               Compound No. 1 (25 μg)                                                     ______________________________________                                    

Forebrain Ischemia Assay

Male Mongolian gerbils, 50-70 gm, were used as subjects. Compound No. 1(30 mg/kg) was injected i.p. 30 minutes prior to carotid occlusion into6 gerbils. In preparation for surgical procedures, the animals werelightly anesthetized with halothane and placed upside down on a heatedpad with their snout within a nosecone. Nitrous oxide (70%): oxygen(30%) plus 0.5% halothane was circulated through the nosecone to providecontinuous anesthesia throughout the surgical procedure. A midlineincision was made in the neck and the carotid arteries were exposed. Alength of suture thread was placed under each carotid. The thread wasthen tightened around each carotid and pressure applied to the thread toinsure flow was occluded. Flow was occluded for 5 minutes and then thethread was removed. The carotids were visually inspected to confirm thatreflow had occurred. The wound was then closed with autoclips and thegerbils allowed to recover. Following surgery, the gerbils were keptalive for 7 days. They were anesthetized with 100 mg/kg sodiumpentobarbital and perfused transcardially with saline (with heparin)followed by buffered formalin. The brain was removed, trimmed andprepared for histological processing. Sections (10 microns) were stainedwith thionin. At 7 days following the ischemic insult, damaged neuronshave been cleared away by glia and the extent of damage can beascertained within the vulnerable CAl region of the hippocampus. Thedegree of lesion in the CAl region of the hippocampus was quantified bycounting the pyramidal cell bodies in a 0.5 mm length of CAl on thesection corresponding to P 1.7 mm in the atlas of Loskota, Lomax andVerity [W. J. Loskota et al, A Stereotaxic Atlas of the Monolian GerbilBrain, Ann Arbor Science Publishers, Ann Arbor, p. 77, (1974)]. The cellloss was significantly reduced in the gerbils given Compound No. 1(p<0.01).

Also embraced within this invention is a class of pharmaceuticalcompositions comprising one or more compounds of Formula I inassociation with one or more non-toxic, pharmaceutically acceptablecarriers and/or diluents and/or adjuvants (collectively referred toherein as "carrier" materials) and, if desired, other activeingredients. The compounds of the present invention may be administeredby any suitable route, preferably in the form of a pharmaceuticalcomposition adapted to such a route, and in a dose effective for thetreatment intended. Therapeutically effective doses of the compounds ofthe present invention required to prevent or arrest the progress of themedical condition are readily ascertained by one of ordinary skill inthe art. The compounds and composition may, for example, be administeredintravascularly, intraperitoneally, subcutaneously, intramuscularly ortopically.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a therapeutically-effective amount of the activeingredient. Examples of such dosage units are tablets or capsules. Asuitable daily dose for a mammal may vary widely depending on thecondition of the patient, body weight and other factors.

The active ingredient may also be administered by injection as acomposition wherein, for example, saline, dextrose or water may be usedas a suitable carrier. A suitable daily dose is from about 0.1 to 100mg/kg body weight injected per day in multiple doses depending on thedisease being treated. A preferred daily dose would be from about 1 to30 mg/kg body weight. Compounds indicated for prophylactic therapy willpreferably be administered in a daily dose generally in a range fromabout 0.1 mg to about 100 mg per kilogram of body weight per day. A morepreferred dosage will be a range from about 1 mg to about 100 mg perkilogram of body weight. Most preferred is a dosage in a range fromabout 1 to about 50 mg per kilogram of body weight per day. A suitabledose can be administered, in multiple sub-doses per day. These sub-dosesmay be administered in unit dosage forms. Typically, a dose or sub-dosemay contain from about 1 mg to about 100 mg of active compound per unitdosage form. A more preferred dosage will contain from about 2 mg toabout 50 mg of active compound per unit dosage form. Most preferred is adosage form containing from about 3 mg to about 25 mg of active compoundper unit dose.

The dosage regimen for treating a disease condition with the compoundsand/or compositions of this invention is selected in accordance with avariety of factors, including the type, age, weight, sex and medicalcondition of the patient, the severity of the disease, the route ofadministration, and the particular compound employed, and thus may varywidely.

For therapeutic purposes, the compounds of this invention are ordinarilycombined with one or more adjuvants appropriate to the indicated routeof administration. If administered per os, the compounds may be admixedwith lactose, sucrose, starch powder, cellulose esters of alkanoicacids, cellulose alkyl esters, talc, stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone,and/or polyvinyl alcohol, and then tableted or encapsulated forconvenient administration. Such capsules or tablets may contain acontrolled-release formulation as may be provided in a dispersion ofactive compound in hydroxypropylmethyl cellulose. Formulations forparenteral administration may be in the form of aqueous or non-aqueousisotonic sterile injection solutions or suspensions. These solutions andsuspensions may be prepared from sterile powders or granules having oneor more of the carriers or diluents mentioned for use in theformulations for oral administration. The compounds may be dissolved inwater, polyethylene glycol, propylene glycol, ethanol, corn oil,cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride,and/or various buffers. Other adjuvants and modes of administration arewell and widely known in the pharmaceutical art.

Although this invention has been described with respect to specificembodiments, the details of these embodiments are not to be construed aslimitations. Various equivalents, changes and modifications may be madewithout departing from the spirit and scope of this invention, and it isunderstood that such equivalent embodiments are part of this invention.

What is claimed is:
 1. A method for treating a patient afflicted by orsusceptible to a neurodegenerative disorder or neurotoxic injury, saidmethod comprising administering to the patient atherapeutically-effective amount of a compound of Formula I: ##STR48##wherein A is ##STR49## wherein each of R¹ and R² is independentlyselected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl,aryl, hydroxyalkyl, alkoxyalkyl and halo; wherein R¹ and R² may be takentogether to form oxo; wherein each of R³ through R⁷ is independentlyselected from hydrido, alkyl, hydroxy, cycloalkyl, cycloalkylalkyl,aralkyl, aryl, alkoxy, alkoxyalkyl, aryloxy, aralkoxy, hydroxyalkyl,halo and haloalkyl; wherein R⁴ and R⁵ may be taken together to form oxo;wherein n is a number selected from zero to five, inclusive; whereineach X is independently one or more groups selected from hydrido,hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy,aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano,amino, monoalkylamino, dialkylamino, nitro, carboxy, carboxyalkyl andalkanoyl; wherein each of R¹⁰ through R¹³ is independently selected fromhydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl,hydroxyalkyl and halo; wherein R¹⁰ and R¹¹ may be taken together to formoxo; wherein R¹² and R¹³ may be taken together to form oxo; wherein eachof p and q is a number selected from one to four, inclusive; wherein Zis selected from O, S, and >N--R¹⁸ ; wherein R¹⁸ may be selected fromhydrido, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl,alkoxyalkyl, hydroxyalkyl, alkanoyl, aralkanoyl, aroyl, aminoalkyl,monoalkylaminoalkyl and dialkylaminoalkyl; wherein R¹⁸ together with oneof R¹⁰ through R¹³ may form a fused heterocyclic ring containing five toabout eight ring members;
 2. The method of claim 1 wherein each of R¹and R² is independently selected from hydrido, alkyl, cycloalkyl,cycloalkylalkyl,or a pharmaceutically-acceptable salt thereof aralkyl,aryl, hydroxyalkyl, alkoxyalkyl and halo; wherein R¹ and R² may be takentogether to form oxo; wherein each of R³ and R⁷ is independentlyselected from hydrido, alkyl, hydroxy, cycloalkyl, cycloalkylalkyl,aralkyl, aryl, alkoxy, alkoxyalkyl, aryloxy, aralkoxy, hydroxyalkyl,halo and haloalkyl; wherein R⁴ and R⁵ may be taken together to form oxo;wherein n is a number selected from zero to five, inclusive; whereineach X is independently one or more groups selected from hydrido,hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy,aralkoxy, aryloxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano,amino, monoalkylamino, dialkylamino, nitro, carboxy, carboxyalkyl andalkanoyl; or a pharmaceutically-acceptable salt thereof.
 3. The methodof claim 2 wherein each of R¹ and R² is independently selected fromhydrido, alkyl, cycloalkyl, cycloalkylalkyl, aralkyl, aryl,hydroxyalkyl, alkoxyalkyl and halo; wherein R¹ and R² may be takentogether to form oxo; wherein each of R³ through R⁷ is independentlyselected from hydrido, alkyl, hydroxy, cycloalkyl, cycloalkylalkyl,phenalkyl, phenyl, alkoxy, alkoxyalkyl, phenoxy, phenalkoxy,hydroxyalkyl, halo and haloalkyl; wherein R⁴ and R⁵ may be takentogether to form oxo; wherein n is a number from zero to five,inclusive; wherein each X is independently one or more groups selectedfrom hydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, phenalkyl,phenyl, alkoxy, phenalkoxy, phenoxy, alkoxyalkyl, haloalkyl,hydroxyalkyl, halo, cyano, amino, monoalkylamino, dialkylamino, carboxy,carboxyalkyl and alkanoyl; or a pharmaceutically-acceptable saltthereof.
 4. The method of claim 3 wherein each of R¹ and R² isindependently selected from hydrido, loweralkyl, phenylloweralkyl,phenyl and loweralkoxy-loweralkyl; wherein R¹ and R² may be takentogether to form oxo; wherein each of R³ through R⁷ is independentlyselected from hydrido, loweralkyl, hydroxy, cycloalkyl of three to eightcarbon atoms, cycloalkylalkyl of four to eight carbon atoms,phenylloweralkyl, phenyl, loweralkoxy, loweralkoxyloweralkyl, phenoxy,phenalkoxy, hydroxyloweralkyl, halo and haloloweralkyl; wherein R⁴ andR⁵ may be taken together to form oxo; wherein n is a number selectedfrom zero to five, inclusive; wherein each X is independently one ormore groups selected from hydrido, hydroxy, loweralkyl, cycloalkyl ofthree to about eight carbon atoms, cycloalkylalkyl of four to abouteight carbon atoms, phenylloweralkyl, phenyl, loweralkoxy, phenoxy,loweralkoxyloweralkyl, haloloweralkyl, hydroxyloweralkyl, halo, carboxy,carboxyloweralkyl and loweralkanoyl; or a pharmaceutically-acceptablesalt thereof.
 5. The method of claim 4 wherein each of R¹ and R² isindependently selected from hydrido, loweralkyl, benzyl and phenyl;wherein R¹ and R² may be taken together to form oxo; wherein n isselected from zero to two, inclusive; wherein each of R³ and R⁷ isindependently selected from hydrido, loweralkyl, hydroxy, benzyl,phenyl, loweralkoxy, phenoxy, benzyloxy, halo and haloloweralkyl;wherein each X is independently one or more groups selected fromhydrido, hydroxy, loweralkyl, benzyl, phenyl, loweralkoxy, phenoxy,haloloweralkyl, halo and loweralkanoyl; or a pharmaceutically-acceptablesalt thereof.
 6. The method of claim 5 wherein each of R¹ and R² isindependently hydrido or methyl; wherein R¹ and R² may be taken togetherto form oxo; wherein each of R³ through R⁷ is independently selectedfrom hydrido, methyl, ethyl, hydroxy, methoxy, halo and trihalomethyl;wherein n is one or two; and wherein each X is independently one or moregroups selected from hydrido, methyl, ethyl, hydroxy, methoxy,trihalomethyl and halo; or a pharmaceutically-acceptable salt thereof.7. The method of claim 1 wherein said compound is selected from a familyof compounds of Formula III: ##STR50## wherein each of R¹, R² and R¹⁰through R¹³ is independently selected from hydrido, alkyl, cycloalkyl,cycloalkylalkyl, aralkyl, aryl, alkoxyalkyl, hydroxyalkyl and halo;wherein R¹⁰ and R¹¹ may be taken together to form oxo; wherein R¹² andR¹³ may be taken together to form oxo; wherein R¹ and R² may be takentogether to form oxo; wherein each of R³ and R⁷ is independentlyselected from hydrido, alkyl, hydroxy, cycloalkyl, cycloalkyl alkyl,aralkyl, aryl, alkoxy, alkoxyalkyl, aryloxy, aralkoxy, hydroxyalkyl,halo and haloalkyl; wherein R⁴ and R⁵ may be taken together to form oxo;wherein n is a number selected from zero to five, inclusive; whereineach of p and q is a number selected from one to four, inclusive;wherein Z is selected from O, S, and >N--R¹⁸ ; wherein R¹⁸ may beselected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heteroaryl, alkoxyalkyl, hydroxyalkyl, alkanoyl, aralkanoyl,aroyl, aminoalkyl, monoalkylaminoalkyl an dialkylaminoalkyl; wherein R¹⁸together with one of R¹⁰ through R¹³ may form a fused heterocyclic ringcontaining five to about eight ring members; wherein each X isindependently one or more groups selected from hydrido, hydroxy, alkyl,cycloalkyl, cycloalkylalkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy,alkoxyalkyl, haloalkyl, hydroxyalkyl, halo, cyano, amino,monoalkylamino, dialkylamino, nitro, carboxy, carboxyalkyl and alkanoyl;or a pharmaceutically-acceptable salt thereof.
 8. The method of claim 7wherein each of R¹, R² and R¹⁰ through R¹³ is independently selectedfrom hydrido, alkyl, cycloalkyl, cycloalkylalkyl, phenalkyl, phenyl,alkoxyalkyl, hydroxyalkyl and halo; wherein R¹ and R² may be takentogether to form oxo; wherein each of R³ through R⁷ is independentlyselected from hydrido, alkyl, hydroxy, cycloalkyl, cycloalkylalkyl,phenalkyl, phenyl, alkoxy, alkoxyalkyl, phenoxy, phenalkoxy,hydroxyalkyl, halo and haloalkyl; wherein R⁴ and R⁵ may be takentogether to form oxo; wherein n is a number from zero to five,inclusive; wherein each of p and q is a number selected from one tofour, inclusive; wherein Z is selected from O, S and >N--R¹⁸ ; whereinR¹⁸ may be selected from hydrido, alkyl, cycloalkyl, cycloalkylalkyl,phenyl, phenalkyl, heteroaryl, alkoxyalkyl, hydroxyalkyl, alkanoyl,phenalkanoyl, aroyl, aminoalkyl, monoalkylaminoalkyl anddialkylaminoalkyl; wherein R¹⁸ together with one of R¹⁰ through R¹³ forma fused heterocyclic ring containing five to about eight ring members;wherein each X is independently one or more groups selected fromhydrido, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, phenalkyl, phenyl,alkoxy, phenalkoxy, phenoxy, alkoxyalkyl, haloalkyl, hydroxyalkyl, halo,cyano, amino, monoalkylamino, dialkylamino, carboxy, carboxyalkyl andalkanoyl; or a pharmaceutically-acceptable salt thereof.
 9. The methodof claim 8 wherein each of R¹⁰ through R¹³ is independently selectedfrom hydrido, loweralkyl, cycloalkyl of three to about eight carbonatoms, cycloalkylalkyl of four to about eight carbon atoms,phenylloweralkyl, phenyl, loweralkoxyloweralkyl, hydroxyloweralkyl andhalo; wherein each of R¹ and R² is independently selected from hydrido,loweralkyl, phenylloweralkyl, phenyl and loweralkoxyloweralkyl; whereinR¹ and R² may be taken together to form oxo; wherein each of R³ throughR⁷ is independently selected from hydrido, loweralkyl, hydroxy,cycloalkyl of three to eight carbon atoms, cycloalkylalkyl of four toeight carbon atoms, phenylloweralkyl, phenyl, loweralkoxy,loweralkoxyloweralkyl, phenoxy, phenalkoxy, hydroxyloweralkyl, halo andhaloloweralkyl; wherein R⁴ and R⁵ may be taken together to form oxo;wherein n is a number selected from zero to five, inclusive; whereineach of p and q is two or three; wherein Z is selected from O, S,>N--R¹⁸ ; wherein R¹⁸ may be selected from hydrido, loweralkyl,cycloalkyl of three to about eight carbon atoms, cycloalkylalkyl of fourto about eight carbon atoms, phenyl, phenylloweralkyl,loweralkoxyloweralkyl, hydroxyloweralkyl, loweralkanoyl and heteroarylselected from saturated, partially unsaturated and fully unsaturatedheterocyclic rings containing five to seven ring members of which one ortwo ring members are selected from oxygen atom and nitrogen atom;wherein R¹⁸ together with one of R¹⁰ through R¹³ may form a fusedheterocyclic ring containing five or six ring members; wherein each X isindependently one or more groups selected from hydrido, hydroxy,loweralkyl, cycloalkyl of three to about eight carbon atoms,cycloalkylalkyl of four to about eight carbon atoms, phenylloweralkyl,phenyl, loweralkoxy, phenoxy, loweralkoxyloweralkyl, haloloweralkyl,hydroxyloweralkyl, halo, carboxy, carboxyloweralkyl and loweralkanoyl;or a pharmaceutically-acceptable salt thereof.
 10. The method of claim 9wherein said compound is selected from a family of compounds of FormulaIV: ##STR51## wherein each of R¹ and R² is independently selected fromhydrido, loweralkyl, benzyl and phenyl; wherein R¹ and R² may be takentogether to form oxo; wherein each of R³ through R⁷ is independentlyselected from hydrido, loweralkyl, hydroxy, benzyl, phenyl, benzyl,loweralkoxy, phenoxy, benzyloxy, halo and haloloweralkyl; wherein R¹⁸may be selected from hydrido, loweralkyl, cycloalkyl of five or sixcarbon atoms, cycloalkylalkyl of six or seven carbon atoms, phenyl,hydroxyloweralkyl, and heteroaryl selected from saturated or fullyunsaturated heterocyclic rings containing five to seven ring members ofwhich one or two ring members are nitrogen atom; wherein each X isindependently one or more groups selected from hydrido, hydroxy,loweralkyl, benzyl, phenyl, loweralkoxy, phenoxy, haloloweralkyl, halo,and loweralkanoyl; and wherein each of R²³ through R³⁰ is independentlyselected from hydrido, loweralkyl, benzyl, phenyl and halo; wherein R¹⁸together with one of R²³, R²⁴, R²⁹ or R³⁰ may form a fused heterocyclicring containing five or six ring members; or apharmaceutically-acceptable salt thereof.
 11. The method of claim 10wherein each of R¹ and R² is independently hydrido or methyl; wherein R¹and R² may be taken together to form oxo; wherein each of R³ through R⁷is independently selected from hydrido, methyl, ethyl, hydroxy, methoxy,halo and trihalomethyl; wherein R¹⁸ is selected from hydrido, methyl,ethyl, hydroxyethyl, benzyl, pyridyl and pyrimidyl; wherein each of R²³through R³⁰ is independently selected from hydrido, methyl, ethyl andtrihalomethyl; wherein R¹⁸ together with one of R²³, R²⁴, R²⁹ or R³⁰ mayform a fused heterocyclic ring containing five or six ring members; andwherein each X is independently one or more groups selected fromhydrido, methyl, ethyl, hydroxy, methoxy, trihalomethyl and halo; or apharmaceuticallyacceptable salt thereof.
 12. The method of claim 11wherein said compound is selected from4-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]1-methylpiperazine;4-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]-1-(2-hydroxyethyl)-piperazine;4-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]-1-(2-pyrimidyl)piperazine;4-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]-1,4-diazabicyclo[4.3.0]-nonane;4-[(9,10-dihydro-9,10-ethanoanthracenyl)carbonyl]-1-methylpiperazine;and 4-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]-1-benzylpiperazine.13. The method of claim 12 wherein said compound is selected from4-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]-1-(2-pyrimidyl)piperazine;4-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]-1,4-diazabicyclo[4.3.0]-nonane;and 4-[(9,10-dihydro-9,10-ethanoanthracenyl)methyl]-1-benzylpiperazine.14. The method of claim 1 wherein said patient is treated for aneurodegenerative disorder.
 15. The method of claim 1 wherein saidpatient is treated for neurotoxic injury.